Ethers of O-Desmethyl venlafaxine

ABSTRACT

This invention provides O-α-acyloxyalkyl ethers of the venlafaxine metabolite 4-[2-(Dimethylamino-1-(1-hydroxycyclohexyl)ethyl]phenol, represented by Formula (I):                    
     wherein: 
     the configuration at the steriogenic center (*) may be R, S, or RS (the racemate); 
     R 1  is selected from C 1 -C 6  alkyl, C 1 -C 6  alkoxy, C 3 -C 6  cycloalkyl, or the moiety:                    
     R 2  is selected from H, or C 1 -C 6  alkyl; or, 
     R 1  and R 2  may be concatenated such that                    
      form a moiety having formula (b):                    
     R3 is selected from H or C 1 -C 6  alkyl; and 
     R4 and R5 are independently selected from H, C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, C 1 -C 6  alkoxy, C 1 -C 6  thioalkoxy, —CN, —OH, —CF 3 , —OCF 3 , halogen, —NH 2 , —NO 2 , or mono or dialkylamino wherein each alkyl group has 1 to 6 carbon atoms, or pharmaceutically acceptable salts or hydrates thereof, R, S, or RS forms thereof; as well as pharmaceutical compositions and methods treating central nervous system disorders.

This application is a divisional application of U.S. Ser. No. 09/722,193filed Nov. 21, 2000 which claims priority from Provisional ApplicationNo. 60/240,922, filed Nov. 24, 1999, the entire disclosure of which ishereby incorporated by reference.

FIELD OF THE INVENTION

This invention provides O-α-acyloxyalkyl ethers of4-[2-(Dimethylamino-1-(1-hydroxycyclohexyl)ethyl]phenol, as well aspharmaceutical compositions and uses thereof.

BACKGROUND OF THE INVENTION

Various patents and literature references describe the biologicalactivities of venlafaxine, and its salts and analogs. Venlafaxinehydrochloride tablets are marketed by Wyeth-Ayerst Laboratories asEFFEXOR.

The absolute configuration of the (+) enantiomer of venlafaxine wasestablished as S by a single crystal X-ray analysis of the hydrobromidesalt and the anomalous dispersion technique (Yardley et al., J. Med.Chem., 1990, 33, 2899).

(R/S)-1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl]cyclohexanol and itsmetabolites 1-[2-(dimethylamino)-1-(4-hydroxyphenyl)ethyl]cyclohexanoland 1-[1-(4-methoxyphenyl)-2-(methylamino)ethyl]cyclohexanol aredisclosed and claimed in U.S. Pat. No. 4,535,186 (Husbands et al.). U.S.Pat. No. 5,530,013 (Husbands et al.) claims the use of venlafaxine inthe inducement of cognition enhancement. U.S. Pat. No. 5,506,270 (Uptonet al.) claims venlafaxine's use in methods of treating hypothalamicamenorrhea in non-depressed women.

U.S. Pat. No. 5,788,986 (Dodman) and U.S. Pat. No. 5,554,383 (Dodman)teaches and claims the use of serotonin reuptake inhibitors in modifyingthe behavior of dogs.

DETAILED DESCRIPTION OF THE INVENTION

This invention provides pharmaceutically active O-α-acyloxyalkyl ethersof the venlafaxine metabolite4-[2-(Dimethylamino-1-(1-hydroxycyclohexyl)ethyl]phenol (“O-Desmethylvenlafaxine” or “ODV”) having the structural formula I

wherein

the configuration at the steriogenic center (*) may be R, S, or RS (theracemate);

R₁ is selected from C₁-C₆ alkyl, C₁-C₆ alkoxy, C₃-C₆ cycloalkyl, or themoiety:

R₂ is selected from H, or C₁-C₆ alkyl; or,

R₁ and R₂ may be concatenated such that

 form a moiety having formula (b):

R3 is selected from H or C₁-C₆ alkyl; and

R4 and R5 are independently selected from H, C₁-C₆ alkyl, C₃-C₆cycloalkyl, C₁-C₆ alkoxy, C₁-C₆ thioalkoxy, —CN, —OH, —CF₃, —OCF₃,halogen, —NH₂, —NO₂, or —N(CH₃)₂, or pharmaceutically acceptable saltsor hydrates thereof.

In some preferred embodiments of the present invention R1 is t-butyl,methoxy, or isobenzofuranone.

In other preferred embodiments of the invention R2 is C1-C3 alkyl and instill more preferred embodiments of the invention R2 is methyl. Specificexamples of compounds of Formula I include:

{4-[2-(dimethylamino)-1-(1-hydroxycyclohexyl)ethyl]phenoxy}methylpivalate;

1-{4-[2-(dimethylamino)-1-(1-hydroxycyclohexyl)ethyl]phenoxy}ethylpropionate; and

3-{4-[2-(dimethylamino)-1-(1-hydroxycyclohexyl)ethyl]phenoxy}-2-benzofuran-1(3H)-one.

Particularly, this invention provides compounds and/or compositions ofboth the O-α-acyloxyalkyl R-ether of Formula I and the O-α-acyloxyalkylS-ether of Formula I, both being substantially free of the other. Inaddition, the invention provides the O-α-acyloxyalkyl RS-ether of4-[2-(Dimethylamino)-1-(1-hydroxycyclohexyl)ethyl]-phenol of Formula I.

Substantially free, as used herein means the compound or composition ismade up of significantly greater proportion of the desired isomer thanof the optical antipode. In a preferred embodiment of the invention,“substantially free” means that the compound or composition is made upof at least about 90% of the desired isomer and about 10% or less of theoptical antipode. In still more preferred embodiments of the presentinvention, the compound or composition is made up of at least about 95%of the desired isomer and about 5% or less of the optical antipode. Inyet further embodiments of the present invention the compound orcomposition is made up of at least about 99% of the desired isomer andabout 1% or less of the optical antipode. Preferably the characterizedor separated enantiomer will exhibit physical properties of a fullycharacterized compound, i.e. a uniform melting point and a uniformrotation of plane-polarized light in a polarimeter. Most preferably, theenantiomers will be recrystallized to analytical purity.

C₁-C₆ alkyl as used herein, such as in the definition of R₁, includesstraight, branched chain alkyl groups within the specified range ofcarbon atoms.

Halogen, as used herein refers to chlorine, bromine, iodine andfluorine.

Pharmaceutically acceptable salts refer to salts prepared frompharmaceutically acceptable acids, including inorganic acids and organicacids, such as, but not limited to, acetic, benzenesulfonic, benzoic,camphorsulfonic, citric, ethenesulfonic, fumaric, gluconic, glutamic,hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic,methanesulfonic, mucic, mitric, pamoic, pantothenic, phosphoric,succinic, sulfuric, tartaric, p-toluenesulfonic and the like.

Compounds of the invention are readily prepared by methods known in theart, for instance, as described by Bodor, et al., J. Org. Chem.(48)5280-5284 (1983).

The appropriate R-, S-, or(R/S)-4-[2-(Dimethylamino-1-(1-hydroxycyclohexyl)ethyl]phenol is reactedwith the appropriate O-α-acyloxyalkyl halide (examples:pivaloyloxymethyl chloride, 3-bromophthalide, iodomethyl pivalate)(Scheme Ia) or (acyloxy)benzyl α-halide (Scheme Ib) in an inert solvent(acetonitrile, tetrahydrofuran, dimethylformamide) in the presence of analkali metal carbonate (sodium or potassium carbonate) or transitionmetal carbonate (silver carbonate) in accordance with Schemes Ia and Ib.

wherein R₁ is selected from C₁-C₆ alkyl, C₁-C₆ alkoxy, C₃-C₆ cycloalkyl,or the moiety:

R₂ is selected from H, or C₁-C₆ alkyl;

or R² and R³ are concatenated to form a moiety having formula (b);

R3 is selected from H or C₁-C₆ alkyl; and

R4 and R5 are independently selected from H, C₁-C₆ alkyl, C₃-C₆cycloalkyl, C₁-C₆ alkoxy, C₁-C₆ thioalkoxy, —CN, —OH, —CF₃, —OCF₃,halogen, —NH₂, —NO₂, or mono or dialkylamino wherein each alkyl grouphas 1 to 6 carbon atoms.

In some preferred embodiments of the invention increased yield may beobtained by reacting the appropriate R-, S-, or(RIS)-4-[2-(Dimethylamino-1-(1-hydroxycyclohexyl)ethyl]phenol with theappropriate O-α-acyloxyalkyliodide in an inert solvent (acetonitrile,tetrahydrofuran, dimethylformamide) in the presence of alkali metalcarbonate such as potassium carbonate, or transition metal carbonatesuch as silver carbonate. Most preferred is the use ofO-α-acyloxyalkyliodide in the presence of silver carbonate at lowtemperatures in the range of approximately 0-5° C.

In a minor modification, compounds of formula I wherein R1 and R2 areconcatenated to form

and one or both of R₄ and R₅ are NH₂, can be obtained by catalyticreductions, such as with palladium catalysts, from corresponding analogswherein R₄ or R₅ are NO₂.

Racemic 1-[2-(dimethylamino)-1-(4-hydroxyphenyl)ethyl]cyclohexanol canbe produced as described in Example 26 of U.S. Pat. No. 4,535,186(Husbands et al.), which is incorporated herein by reference. It will beunderstood that the enantiomers may be separated from each other bystandard resolution techniques known in the art.

Alternatively, these R and S enantiomers may be obtained byO-demethylation of the separated enantiomers of venlafaxine using eitherboron tribromide or ethane thiol anion.

O-α-acyloxyalkyl ethers of Formula I and their pharmaceutically usefulsalts and hydrates are useful for the biological and pharmacologicalactivities for which venlafaxine and its salts are known in the art.These O-α-acyloxyalkyl ethers may be used in treating or inhibitingcentral nervous system disorders, including depression, (including butnot limited to major depressive disorder, biopolar disorder, anddysthymia), fibromyalgia, anxiety, panic disorder, agoraphobia,post-traumatic stress disorder, premenstrual dysphoric disorder (alsoknown as pre-menstrual syndrome), attention deficit disorder (with andwithout hyperactivity), obsessive compulsive disorder (includingtrichotillomania), social anxiety disorder, generalized anxietydisorder, autism, schizophrenia, obesity, anorexia nervosa, bulimianervosa, Gilles de la Tourette Syndrome, vasomotor flushing, cocaine andalcohol addiction, sexual dysfunction (including premature ejaculation),borderline personality disorder, chronic fatigue syndrome, urinaryincontinence, pain (including but not limited to migraine, chronic backpain, phantom limb pain, central pain, neuropathic pain such as diabeticneuropathy and postherpetic neuropathy), Raynaud's syndrome, and others.These compounds are also useful in the inducement of cognitionenhancement and in regimens for cessation of smoking or other tobaccouses.

This invention also includes methods of treating, preventing, inhibitingor alleviating each of the maladies listed above in a mammal, preferablyin a human, the methods comprising providing a pharmaceuticallyeffective amount of a compound of this invention to the mammal in needthereof.

“Providing” as used herein with respect to providing a compound orsubstance covered by the invention, means either directly administeringsuch a compound or substance, or administering a prodrug, derivative oranalog which forms an equivalent amount of the compound or substancewithin the body.

A pharmaceutically effective dose will include those doses which providethe relief or prevention sought for the malady in question. Thecompounds of this invention may be provided in the dosages andpharmaceutical formulations known in the art as useful for venlafaxinehydrochloride (such as those doses known for the venlafaxinehydrochloride products marketed by Wyeth-Ayerst Laboratories under theEffexor® trademark). It will be understood that the initial dose,increases therefrom and final daily administration will be determined bya medical professional considering the needs and conditions for eachrecipient. For instance, a daily dose for an adult human may be fromabout 75 mg to about 450 mg per day, preferably between about 75 andabout 225 mg per day. An initial dose of 75 mg per day may beadministered, with increases as determined by a medical professional.

This invention also includes pharmaceutical compositions comprising apharmaceutically effective amount of a compound of this invention andone or more pharmaceutically acceptable carriers or excipients. Apreferred method of administration includes the use of the presentcompounds in extended release formulations of the type described inpublished PCT application WO 99/22724 (Sherman et al.)., which isincorporated herein by reference.

The present invention is exemplified, but not limited by, the followingspecific examples.

EXAMPLE 1 {4-[2-(Dimethylamino)-1-(1-hydroxycyclohexyl)ethyl]phenoxy}methyl Pivalate

4-[2-(Dimethylamino)-1-(1-hydroxycyclohexyl)ethyl]phenol (1 g, 3.79mmol), chloromethyl pivalate (0.75 g, 5 mmol), anhydrous K₂CO₃(0.7 g, 5mmol) and KI (75 mg, 0.5 mmol) were stirred in acetonitrile (50 mL) andrefluxed overnight. The solvent was evaporated and the residue waspartitioned between ethyl acetate and water. The ethyl acetate was dried(MgSO₄) and evaporated to give the title compound as a minor component.

IR (KBr) 1758 cm⁻¹. MS(+)FAB[M+H]⁺378.3 calcd. For C₂₂H₃₅NO₄ 377.

EXAMPLE 2{4-[2-(Dimethylamino)-1-(1-hydroxycyclohexyl)ethyl]phenoxy}methylPivalate

To a solution of ODV (2.0 g, 7.6 mmol) and silver carbonate (8.4 g, 30.4mmol) in acetonitrile (60 mL) at 0° C. was added a solution ofiodomethyl pivalate (prepared as described by Bodor, et al., J. Org.Chem. 1983, 48, 5280-5284.) (3.4 g, 14.0 mmol) in acetonitrile (100 mL)dropwise over 4 hr. The reaction mixture was filtered throughdiatomaceous earth (CELITE, Celite Corporation, Lompoc, Calif.), thenabsorbed onto a activated magnesium silicate (60-100 mesh) (FLORISIL,U.S. Silica Company) and purified by column chromatography (FLORISIL,ethyl acetate: acetonitrile 9:1) to afford the title compound (0.87 g,45%, based on 68% conversion) as a yellow tinted semi-solid: ¹H NMR(CD₃CN) δ 0.78-1.0 (m, 2H), 1.19 (s, 9H), 1.15-1.35 (m, 4H), 1.4-1.7 (m,4H), 2.2 (s, 6H), 2.25 (dd, J=11.2, 4.5 Hz, 1H), 2.94 (dd, J=11.2, 4.5Hz, 1H), 3.22 (t, J=11.2 Hz, 1H), 5.7 (s, 2H), 6.95 (d, J=8.7 Hz, 1H),7.13 (d, J=8.7 Hz, 1H); ¹³C-NMR (CD₃CN) δ 22.22, 22.44, 26.91, 27.10(t), 32.83, 38.78 (t), 39.55 (s), 45.71 (q), 52.58, 61.74, 74.45 (d),86.78 (t), 116.54, 131.48 (d), 136.68, 156.44, 178.05 (s); MS (ESI) m/z378 (M+H)⁺; further characterized as the maleate salt. Anal.(C₂₆H₃₉NO₈-0.25H₂O) Calc: C: 62.69, H: 7.99, N: 2.81, Found: C: 62.68,H: 7.68, N: 2.65.

The celite cake was taken up in brine and extracted with ethyl acetate.Evaporation of the solvent affords 0.65 g (33%) recovered ODV.

EXAMPLE 3 4-[(1R)-2-(Dimethylamino)-1-(1-hydroxycyclohexyl)ethyl]phenylPivalate

To a solution of ODV (3.0 g, 11.4 mmol) and silver carbonate (12.6 g,45.6 mmol) in acetonitrile (300 mL) at 0° C. was added a solution ofiodomethyl pivalate (prepared as described by Bodor, et al., J. Org.Chem. 1983, 48, 5280-5284.) (6.9 g, 28.5 mmol) in acetonitrile (40 mL)in eight equal portions over 16 hr. The reaction mixture was filteredthrough diatomaceous earth (CELITE, Celite Corporation, Lompoc, Calif.),then absorbed onto activated magnesium silicate (60-100 mesh) (FLORISIL,U.S. Silica Company) and purified by column chromatography (FLORISIL,ethyl acetate: acetonitrile 9:1) to afford the title compound (1.15 g,39%, based on 60% conversion) as a white foam: ¹H NMR (CD₃CN) δ 0.78-1.0(m, 2H), 1.19 (s, 9H), 1.15-1.35 (m, 4H), 1.4-1.7 (m, 4H), 2.2 (s, 6H),2.25 (dd, J=11.2, 4.5 Hz, 1H), 2.94 (dd, J=11.2, 4.5 Hz, 1H), 3.22 (t,J=11.2 Hz, 1H), 5.7 (s, 2H), 6.95 (d, J=8.7 Hz, 1H), 7.13 (d, J=8.7 Hz,1H); ¹³C-NMR (CD₃CN) δ 22.22, 22.44, 26.91, 27.10 (t), 32.83, 38.78 (t),39.55 (s), 45.71 (q), 52.58, 61.74, 74.45 (d), 86.78 (t), 116.54, 131.48(d), 136.68, 156.44, 178.05 (s); [α]²⁰ _(D) −5.95° (c 1.00, MeOH); MS(ESI) m/z 378 (M+H)+.

The CELITE cake was taken up in brine and extracted with ethyl acetate.Evaporation of the solvent affords 1.2 g (40%) recovered ODV.

EXAMPLE 4 4-[(1S)-2-(Dimethylamino)-1-(1-hydroxycyclohexyl)ethyl]phenylPivalate

To a solution of ODV (4.0 g, 15.2 mmol) and silver carbonate (16.8 g,60.8 mmol) in acetonitrile (400 mL) at 0° C. was added a solution ofiodomethyl pivalate (prepared as described by Bodor, et al., J. Org.Chem. 1983, 48, 5280-5284.) (8.3 g, 34.3 mmol) in acetonitrile (150 mL)over a 9 hr period. The reaction mixture was filtered throughdiatomaceous earth (CELITE, Celite Corporation, Lompoc, Calif.), thenabsorbed onto activated magnesium silicate (60-100 mesh) (FLORISIL, U.S.Silica Company) and purified by column chromatography (FLORISIL, ethylacetate: acetonitrile 9:1) to afford the title compound (1.58 g, 48%,based on 57% conversion) as a clear viscous oil: ¹H NMR (CD₃CN) δ0.78-1.0 (m, 2H), 1.19 (s, 9H), 1.15-1.35 (m, 4H), 1.4-1.7 (m, 4H), 2.2(s, 6H), 2.25 (dd, J=11.2, 4.5 Hz, 1H), 2.94 (dd, J=11.2, 4.5 Hz, 1H),3.22 (t, J=11.2 Hz, 1H), 5.7 (s, 2H), 6.95 (d, J=8.7 Hz, 1H), 7.13 (d,J=8.7 Hz, 1H); ¹³C-NMR (CD₃CN) δ 22.22, 22.44, 26.91, 27.10 (t), 32.83,38.78 (t), 39.55 (s), 45.71 (q), 52.58, 61.74, 74.45 (d), 86.78 (t),116.54, 131.48 (d), 136.68, 156.44, 178.05 (s); [α]²⁰ _(D) +7.23° (c1.00, MeOH); MS (ESI) m/z 378 (M+H)+.

The CELITE cake was taken up in brine and extracted with ethyl acetate.Evaporation of the solvent affords 1.7 g (43%) recovered ODV.

EXAMPLE 5{4-[2-(Dimethylamino)-1-(1-hydroxycyclohexyl)ethyl]phenoxy}methylPivalate Maleate Salt

To a solution of{4-[2-(dimethylamino)-1-(1-hydroxycyclohexyl)ethyl]phenoxy}methylpivalate (0.032 g, 0.085 mmol) prepared as described in Example 1, inTHF (1.0 mL) at RT was added a solution of maleic acid (0.007 g, 0.06mmol) in THF (1.0 mL). The mixture was warmed and diluted with hexane.The solution was cooled and the resulting crystals filtered off givingthe desired maleate salt as a white solid: mp 112-113° C., ¹H NMR(DMSO-d₆) δ 0.9-1.6 (m, 10H), 1.13 (s, 9H), 2.7 (br.s, 6H), 2.97 (m,1H), 3.55 (m, 2H), 4.59 (br.s, 1H), 5.78 (s, 2H), 6.02 (s, 2H), 7.03 (d,J=8.6 Hz, 1H), 7.33 (d, J=8.6 Hz, 1H), 8.4 (br.s, 1H); MS (ESI) m/z 378(M+H)+; (C₂₆H₃₉NO₈-0.25H₂O) Calc: C: 62.69, H: 7.99, N: 2.81, Found: C:62.68, H: 7.68, N: 2.65.

What is claimed:
 1. A compound of the Formula (I):

wherein the configuration at the steriogenic center (*) is R, S, or RS(the racemate); R₁ and R₂ are concatenated such that

 form a moiety having formula (b):

 and R4 and R5 are independently selected from H, C₁-C₆ alkyl, C₃-C₆cycloalkyl, C₁-C₆ alkoxy, C₁-C₆ thioalkoxy, —CN, —OH, —CF₃, —OCF₃,halogen, —NH₂, —NO₂, or mono or dialkylamino wherein each alkyl grouphas 1 to 6 carbon atoms, or pharmaceutically acceptable salts orhydrates thereof.
 2. A compound of claim 1 which is3-{4-[2-(dimethylamino)-1-(1-hydroxycyclohexyl)ethyl]phenoxy}-2-benzofuran-1(3H)-one,or a pharmaceutically acceptable salt or hydrate thereof.
 3. Apharmaceutical composition comprising a pharmaceutically effectiveamount of a compound of Formula I

wherein the configuration at the steriogenic center (*) is R, S, or RS(the racemate); R₁ and R₂ are concatenated such that

 form a moiety having formula (b):

 and R4 and R5 are independently selected from H, C₁-C₆ alkyl, C₃-C₆cycloalkyl, C₁-C₆ alkoxy, C₁-C₆ thioalkoxy, —CN, —OH, —CF₃, —OCF₃,halogen, —NH₂, —NO₂, or mono or dialkylamino wherein each alkyl grouphas 1 to 6 carbon atoms, or pharmaceutically acceptable salts orhydrates thereof; and a pharmaceutically acceptable carrier orexcipient.
 4. A method of treating depression in a mammal, the methodcomprising providing to a mammal in need thereof a pharmaceuticallyeffective amount of a compound of Formula I

wherein the configuration at the steriogenic center (*) is R, S, or RS(the racemate); R₁ and R₂ are concatenated such that

 form a moiety having formula (b):

 and R4 and R5 are independently selected from H, C₁-C₆ alkyl, C₃-C₆cycloalkyl, C₁-C₆ alkoxy, C₁-C₆ thioalkoxy, —CN, —OH, —CF₃, —OCF₃,halogen, —NH₂, —NO₂, or mono or dialkylamino wherein each alkyl grouphas 1 to 6 carbon atoms, or pharmaceutically acceptable salts orhydrates thereof.
 5. The method of claim 4 wherein the mammal is ahuman.
 6. A method of treating generalized anxiety in a mammal, themethod comprising providing to a mammal in need thereof apharmaceutically effective amount of a compound of Formula I

wherein the configuration at the steriogenic center (*) is R, S, or RS(the racemate); R₁ and R₂ are concatenated such that

 form a moiety having formula (b):

 and R4 and R5 are independently selected from H, C₁-C₆ alkyl, C₃-C₆cycloalkyl, C₁-C₆ alkoxy, C₁-C₆ thioalkoxy, —CN, —OH, —CF₃, —OCF₃,halogen, —NH₂, —NO₂, or mono or dialkylamino wherein each alkyl grouphas 1 to 6 carbon atoms, or pharmaceutically acceptable salts orhydrates thereof.
 7. The method of claim 6 wherein the mammal is ahuman.
 8. A method of treating panic disorder in a mammal, the methodcomprising providing to a mammal in need thereof a pharmaceuticallyeffective amount of a compound of Formula I

wherein the configuration at the steriogenic center (*) is R, S, or RS(the racemate); R₁ and R₂ are concatenated such that

 form a moiety having formula (b):

 and R4 and R5 are independently selected from H, C₁-C₆ alkyl, C₃-C₆cycloalkyl, C₁-C₆ alkoxy, C₁-C₆ thioalkoxy, —CN, —OH, —CF₃, —OCF₃,halogen, —NH₂, —NO₂, or mono or dialkylamino wherein each alkyl grouphas 1 to 6 carbon atoms, or pharmaceutically acceptable salts orhydrates thereof.
 9. The method of claim 8 wherein the mammal is ahuman.
 10. A method of treating post traumatic stress disorder in amammal, the method comprising providing to a mammal in need thereof apharmaceutically effective amount of a compound of Formula I

wherein the configuration at the steriogenic center (*) is R, S, or RS(the racemate); R₁ and R₂ are concatenated such that

 form a moiety having formula (b):

 and R4 and R5 are independently selected from H, C₁-C₆ alkyl, C₃-C₆cycloalkyl, C₁-C₆ alkoxy, C₁-C₆ thioalkoxy, —CN, —OH, —CF₃, —OCF₃,halogen, —NH₂, —NO₂, or mono or dialkylamino wherein each alkyl grouphas 1 to 6 carbon atoms, or pharmaceutically acceptable salts orhydrates thereof.
 11. The method of claim 10 wherein the mammal is ahuman.
 12. A method of treating attention deficit disorder in a mammal,the method comprising providing to a mammal in need thereof apharmaceutically effective amount of a compound of Formula I

wherein the configuration at the steriogenic center (*) is R, S, or RS(the racemate); R₁ and R₂ are concatenated such that

 form a moiety having formula (b):

 and R4 and R5 are independently selected from H, C₁-C₆ alkyl, C₃-C₆cycloalkyl, C₁-C₆ alkoxy, C₁-C₆ thioalkoxy, —CN, —OH, —CF₃, —OCF₃,halogen, —NH₂, —NO₂, or mono or dialkylamino wherein each alkyl grouphas 1 to 6 carbon atoms, or pharmaceutically acceptable salts orhydrates thereof.
 13. The method of claim 12 wherein the mammal is ahuman.
 14. A method of treating anxiety in a mammal, the methodcomprising providing to a mammal in need thereof a pharmaceuticallyeffective amount of a compound of Formula I

wherein the configuration at the steriogenic center (*) is R, S, or RS(the racemate); R₁ and R₂ are concatenated such that

 form a moiety having formula (b):

 and R4 and R5 are independently selected from H, C₁-C₆ alkyl, C₃-C₆cycloalkyl, C₁-C₆ alkoxy, C₁-C₆ thioalkoxy, —CN, —OH, —CF₃, —OCF₃,halogen, —NH₂, —NO₂, or mono or dialkylamino wherein each alkyl grouphas 1 to 6 carbon atoms, or pharmaceutically acceptable salts orhydrates thereof.
 15. The method of claim 14 wherein the mammal is ahuman.
 16. A method of treating schizophrenia in a mammal, the methodcomprising providing to a mammal in need thereof a pharmaceuticallyeffective amount of a compound of Formula I

wherein the configuration at the steriogenic center (*) is R, S, or RS(the racemate); R₁ and R₂ are concatenated such that

 form a moiety having formula (b):

 and R4 and R5 are independently selected from H, C₁-C₆ alkyl, C₃-C₆cycloalkyl, C₁-C₆ alkoxy, C₁-C₆ thioalkoxy, —CN, —OH, —CF₃, —OCF₃,halogen, —NH₂, —NO₂, or mono or dialkylamino wherein each alkyl grouphas 1 to 6 carbon atoms, or pharmaceutically acceptable salts orhydrates thereof.
 17. The method of claim 16 wherein the mammal is ahuman.
 18. A method of treating pain in a mammal, the method comprisingproviding to a mammal in need thereof a pharmaceutically effectiveamount of a compound of Formula I

wherein the configuration at the steriogenic center (*) is R, S, or RS(the racemate); R₁ and R₂ are concatenated such that

 form a moiety having formula (b):

 and R4 and R5 are independently selected from H, C₁-C₆ alkyl, C₃-C₆cycloalkyl, C₁-C₆ alkoxy, C₁-C₆ thioalkoxy, —CN, —OH, —CF₃, —OCF₃,halogen, —NH₂, —NO₂, or mono or dialkylamino wherein each alkyl grouphas 1 to 6 carbon atoms, or pharmaceutically acceptable salts orhydrates thereof.
 19. The method of claim 18 wherein the mammal is ahuman.